Conditional deletion of miR-204 and miR-211 in murine retinal pigment epithelium results in retinal degeneration.

MicroRNAs (miRs) are short, evolutionarily conserved non-coding RNAs that canonically downregulate expression of target genes. The miR family composed of miR-204 and miR-211 is among the most highly expressed in the retinal pigment epithelium (RPE) in both mouse and human, and also retains high sequence identity. To assess the role of this miR family in the developed mouse eye, we generated two floxed conditional knockout mouse lines crossed to the RPE65-ERT2-Cre driver mouse line to perform an RPE-specific conditional knockout of this miR family in adult mice. After Cre-mediated deletion, we observed retinal structural changes by optical coherence tomography; dysfunction and loss of photoreceptors by retinal imaging; and retinal inflammation marked by subretinal infiltration of immune cells by imaging and immunostaining. Single-cell RNA sequencing of diseased RPE and retinas showed potential miR-regulated target genes, as well as changes in non-coding RNAs in the RPE, rod photoreceptors, and Müller glia. This work thus highlights the role of miR-204 and miR-211 in maintaining RPE function and how the loss of miRs in the RPE exerts effects on the neural retina, leading to inflammation and retinal degeneration.

Genetic manipulation of rod-cone differences in mouse retina.

Though rod and cone photoreceptors use similar phototransduction mechanisms, previous model calculations have indicated that the most important differences in their light responses are likely to be differences in amplification of the G-protein cascade, different decay rates of phosphodiesterase (PDE) and pigment phosphorylation, and different rates of turnover of cGMP in darkness. To test this hypothesis, we constructed TrUx;GapOx rods by crossing mice with decreased transduction gain from decreased transducin expression, with mice displaying an increased rate of PDE decay from increased expression of GTPase-activating proteins (GAPs). These two manipulations brought the sensitivity of TrUx;GapOx rods to within a factor of 2 of WT cone sensitivity, after correcting for outer-segment dimensions. These alterations did not, however, change photoreceptor adaptation: rods continued to show increment saturation though at a higher background intensity. These experiments confirm model calculations that rod responses can mimic some (though not all) of the features of cone responses after only a few changes in the properties of transduction proteins.

CAR-T cell therapy targeting surface expression of TYRP1 to treat cutaneous and rare melanoma subtypes.

A major limitation to developing chimeric antigen receptor (CAR)-T cell therapies for solid tumors is identifying surface proteins highly expressed in tumors but not in normal tissues. Here, we identify Tyrosinase Related Protein 1 (TYRP1) as a CAR-T cell therapy target to treat patients with cutaneous and rare melanoma subtypes unresponsive to immune checkpoint blockade. TYRP1 is primarily located intracellularly in the melanosomes, with a small fraction being trafficked to the cell surface via vesicular transport. We develop a highly sensitive CAR-T cell therapy that detects surface TYRP1 in tumor cells with high TYRP1 overexpression and presents antitumor activity in vitro and in vivo in murine and patient-derived cutaneous, acral and uveal melanoma models. Furthermore, no systemic or off-tumor severe toxicities are observed in an immunocompetent murine model. The efficacy and safety profile of the TYRP1 CAR-T cell therapy supports the ongoing preparation of a phase I clinical trial.

Male and Female Discrepancies in Anxiety, Depressive Symptoms, and Coping Strategies among Orthognathic Patients: A Cross-Sectional Analysis.

With an increasing understanding of the differences between men and women's psychological experiences, this study aimed to probe the sex-based differences in anxiety, depressive symptoms, and coping strategies among orthognathic patients. The study hypothesis was that female patients would show higher levels of anxiety and depressive symptoms than males, and that coping mechanisms would differ between male and female sexes. A cross-sectional design was adopted, examining orthognathic patients from the Department of Oral and Maxillo-Facial Surgery at the Emergency Clinical Municipal Hospital in Timisoara, Romania, from 2020 to 2023. Eligible participants (18+ years with no prior orthognathic treatment) completed a comprehensive online questionnaire 6 weeks before scheduled surgery. This was composed of validated self-report instruments comprising the SF-36, GAD-7, and the PHQ-9, and the COPE-60, along with additional sociodemographic data. Of the 127 orthognathic patients analyzed (68 men and 59 women, aged 18 to 65 years, mean age 32), men rated their physical health status slightly better on the SF-36 scale. However, the most notable difference was in mental health, with females scoring higher on both the PHQ-9 (indicative of depression) and the GAD-7 (indicative of anxiety) scales. Specifically, female participants exhibited average PHQ-9 scores 1.8 points higher and GAD-7 scores 1.5 points higher than their male counterparts. Coping mechanisms also varied: 42% of male patients primarily employed "Disengagement" strategies, while 58% of females predominantly used "Engagement" and "Emotion Focused" strategies. Emotion-focused coping was associated with a 1.6-fold increased risk of depressive symptoms. Sex differences play a crucial role in the psychological experiences of orthognathic patients, evident in anxiety and depression levels, perceived health status, and coping strategies. This underlines the importance of sex-tailored psychological support in the preoperative phase for orthognathic surgery patients.

Membrane Attack Complex Mediates Retinal Pigment Epithelium Cell Death in Stargardt Macular Degeneration.

Recessive Stargardt disease (STGD1) is an inherited retinopathy caused by mutations in the ABCA4 gene. The ABCA4 protein is a phospholipid-retinoid flippase in the outer segments of photoreceptors and the internal membranes of retinal pigment epithelial (RPE) cells. Here, we show that RPE cells derived via induced pluripotent stem-cell from a molecularly and clinically diagnosed STGD1 patient exhibited reduced ABCA4 protein and diminished activity compared to a normal subject. Consequently, STGD1 RPE cells accumulated intracellular autofluorescence-lipofuscin and displayed increased complement C3 activity. The level of C3 inversely correlated with the level of CD46, an early negative regulator of the complement cascade. Persistent complement dysregulation led to deposition of the membrane attack complex on the surface of RPE cells, decrease in transepithelial resistance, and subsequent cell death. These findings are strong evidence of complement-mediated RPE cell damage in STGD1, in the absence of photoreceptors, caused by reduced CD46 regulatory protein.

Medial deviation of the pterygoid hamulus as an uncommon cause of persistent oral and facial pain - a rare case report and literature review.

BACKGROUND: Pterygoid hamulus syndrome, a painful oral and facial syndrome, has been described in literature to be correlated with morphological changes in the length of the pterygoid hamulus of the sphenoid bone. CLINICAL PRESENTATION: The current case report describes the treatment for severe, continuous pain in the posterior right palate. Despite numerous conservative treatments given to the patient, no improvement was seen. Cone beam computed tomography (CBCT) measurements revealed an elongation as well as a significant medial deviation of the lower extremity of the medial pterygoid plate. The surgical resection was performed under local anesthesia. The pain subsided two days after the surgery, and there were no relapses in the weeks that followed. CONCLUSION: The medial deviation of the hamulus appeared to be important in the etiology of this painful syndrome. Additional research based on CBCT measurements will be required.

Dawn and dusk peaks of outer segment phagocytosis, and visual cycle function require Rab28.

RAB28 is a farnesylated, ciliary G-protein. Patient variants in RAB28 are causative of autosomal recessive cone-rod dystrophy (CRD), an inherited human blindness. In rodent and zebrafish models, the absence of Rab28 results in diminished dawn, photoreceptor, outer segment phagocytosis (OSP). Here, we demonstrate that Rab28 is also required for dusk peaks of OSP, but not for basal OSP levels. This study further elucidated the molecular mechanisms by which Rab28 controls OSP and inherited blindness. Proteomic profiling identified factors whose expression in the eye or whose expression at dawn and dusk peaks of OSP is dysregulated by loss of Rab28. Notably, transgenic overexpression of Rab28, solely in zebrafish cones, rescues the OSP defect in rab28 KO fish, suggesting rab28 gene replacement in cone photoreceptors is sufficient to regulate Rab28-OSP. Rab28 loss also perturbs function of the visual cycle as retinoid levels of 11-cRAL, 11cRP, and atRP are significantly reduced in larval and adult rab28 KO retinae (p < .05). These data give further understanding on the molecular mechanisms of RAB28-associated CRD, highlighting roles of Rab28 in both peaks of OSP, in vitamin A metabolism and in retinoid recycling.

GFAPδ: A Promising Biomarker and Therapeutic Target in Glioblastoma.

GFAPδ, the delta isoform of the glial fibrillary acidic protein, is mainly expressed in the subventricular zone of the brain, together with other neural stem cell markers like nestin. The authors of this paper were among the first that described in detail the expression of GFAPδ and its correlation with malignancy and invasiveness in cerebral astrocytoma. Later, several papers confirmed these findings, showing that the alternative splice variant GFAPδ is overexpressed in glioblastoma (CNS WHO grade 4) compared with lower grade gliomas. Other studies suggested that a high GFAPδ/α ratio is associated with a more malignant and invasive behavior of glioma cells. Moreover, the changing of GFAPδ/α ratio affects the expression of high-malignant genes. It is now suggested that discriminating between predominant GFAP isoforms, GFAPδ or GFAPα, is useful for assessing the malignancy state of astrocytoma, and may even contribute to the classification of gliomas. Therefore, the purpose of this paper is to review the literature with emphasize on the role of GFAPδ as a potential biomarker, and as a possible therapeutic target in glioblastoma.

Assessing Variant Causality and Severity Using Retinal Pigment Epithelial Cells Derived from Stargardt Disease Patients.

Purpose: Modern molecular genetics has revolutionized gene discovery, genetic diagnoses, and precision medicine yet many patients remain unable to benefit from these advances as disease-causing variants remain elusive for up to half of Mendelian genetic disorders. Patient-derived induced pluripotent stem (iPS) cells and transcriptomics were used to identify the fate of unsolved ABCA4 alleles in patients with Stargardt disease. Methods: Multiple independent iPS lines were generated from skin biopsies of three patients with Stargardt disease harboring a single identified pathogenic ABCA4 variant. Derived retinal pigment epithelial cells (dRPE) from a normal control and patient cells were subjected to RNA-Seq on the Novaseq6000 platform, analyzed using DESeq2 with calculation of allele specific imbalance from the pathogenic or a known linked variant. Protein analysis was performed using the automated Simple Western system. Results: Nine dRPE samples were generated, with transcriptome analysis on eight. Allele-specific expression indicated normal transcripts expressed from splice variants albeit at low levels, and missense transcripts expressed at near-normal levels. Corresponding protein was not easily detected. Patient phenotype correlation indicated missense variants expressed at high levels have more deleterious outcomes. Transcriptome analysis suggests mitochondrial membrane biodynamics and the unfolded protein response pathway may be relevant in Stargardt disease. Conclusions: Patient-specific iPS-derived RPE cells set the stage to assess non-expressing variants in difficult-to-detect genomic regions using easily biopsied tissue. Translational Relevance: This "Disease in a Dish" approach is likely to enhance the ability of patients to participate in and benefit from clinical trials while providing insights into perturbations in RPE biology.

Reproducibility of the Rod Photoreceptor Response Depends Critically on the Concentration of the Phosphodiesterase Effector Enzyme.

The high sensitivity of night vision requires that rod photoreceptors reliably and reproducibly signal the absorption of single photons, a process that depends on tight regulation of intracellular cGMP concentration through the phototransduction cascade. Here in the mouse (Mus musculus), we studied a single-site D167A mutation of the gene for the α subunit of rod photoreceptor phosphodiesterase (PDEA), made with the aim of removing a noncatalytic binding site for cGMP. This mutation unexpectedly eliminated nearly all PDEA expression and reduced expression of the ß subunit (PDEB) to ∼5%-10% of WT. The remaining PDE had nearly normal specific activity; degeneration was slow, with 50%-60% of rods remaining after 6 months. Responses were larger and more sensitive than normal but slower in rise and decay, probably from slower dark turnover of cGMP. Remarkably, responses became much less reproducible than WT, with response variance increasing for amplitude by over 10-fold, and for latency and time-to-peak by >100-fold. We hypothesize that the increase in variance is the result of greater variability in the dark-resting concentration of cGMP, produced by spatial and temporal nonuniformity in spontaneous PDE activity. This variability decreased as stimuli were made brighter, presumably because of greater spatial uniformity of phototransduction and the approach to saturation. We conclude that the constancy of the rod response depends critically on PDE expression to maintain adequate spontaneous PDE activity, so that the concentration of second messenger is relatively uniform throughout the outer segment.SIGNIFICANCE STATEMENT Rod photoreceptors in the vertebrate retina reliably signal the absorption of single photons of light by generating responses that are remarkably reproducible in amplitude and waveform. We show that this reproducibility depends critically on the concentration of the effector enzyme phosphodiesterase (PDE), which metabolizes the second messenger cGMP and generates rod light responses. In rods with the D167A mutation of the α subunit of PDE, only 5%-10% of PDE is expressed. Single-photon responses then become much more variable than in WT rods. We think this variability is caused by spatial and temporal inhomogeneity in the concentration of cGMP in darkness, so that photons absorbed in different parts of the cell produce responses of greatly varying amplitude and waveform.

Lipofuscin causes atypical necroptosis through lysosomal membrane permeabilization.

Lipofuscin granules enclose mixtures of cross-linked proteins and lipids in proportions that depend on the tissue analyzed. Retinal lipofuscin is unique in that it contains mostly lipids with very little proteins. However, retinal lipofuscin also presents biological and physicochemical characteristics indistinguishable from conventional granules, including indigestibility, tendency to cause lysosome swelling that results in rupture or defective functions, and ability to trigger NLRP3 inflammation, a symptom of low-level disruption of lysosomes. In addition, like conventional lipofuscins, it appears as an autofluorescent pigment, considered toxic waste, and a biomarker of aging. Ocular lipofuscin accumulates in the retinal pigment epithelium (RPE), whereby it interferes with the support of the neuroretina. RPE cell death is the primary cause of blindness in the most prevalent incurable genetic and age-related human disorders, Stargardt disease and age-related macular degeneration (AMD), respectively. Although retinal lipofuscin is directly linked to the cell death of the RPE in Stargardt, the extent to which it contributes to AMD is a matter of debate. Nonetheless, the number of AMD clinical trials that target lipofuscin formation speaks for the potential relevance for AMD as well. Here, we show that retinal lipofuscin triggers an atypical necroptotic cascade, amenable to pharmacological intervention. This pathway is distinct from canonic necroptosis and is instead dependent on the destabilization of lysosomes. We also provide evidence that necroptosis is activated in aged human retinas with AMD. Overall, this cytotoxicity mechanism may offer therapeutic targets and markers for genetic and age-related diseases associated with lipofuscin buildups.

Global Collaborative Social Network (Share4Rare) to Promote Citizen Science in Rare Disease Research: Platform Development Study.

BACKGROUND: Rare disease communities are spread around the globe and segmented by their condition. Little research has been performed on the majority of rare diseases. Most patients who are affected by a rare disease have no research on their condition because of a lack of knowledge due to absence of common groups in the research community. OBJECTIVE: We aimed to develop a safe and secure community of rare disease patients, without geographic or language barriers, to promote research. METHODS: Cocreation design methodology was applied to build Share4Rare, with consultation and input through workshops from a variety of stakeholders (patients, caregivers, clinicians, and researchers). RESULTS: The workshops allowed us to develop a layered version of the platform based on educating patients and caregivers with publicly accessible information, a secure community for the patients and caregivers, and a research section with the purpose of collecting patient information for analysis, which was the core and final value of the platform. CONCLUSIONS: Rare disease research requires global collaboration in which patients and caregivers have key roles. Collective intelligence methods implemented in digital platforms reduce geographic and language boundaries and involve patients in a unique and universal project. Their contributions are essential to increase the amount of scientific knowledge that experts have on rare diseases. Share4Rare has been designed as a global platform to facilitate the donation of clinical information to foster research that matters to patients with rare conditions. The codesign methods with patients have been essential to create a patient-centric design.

Multiple strokes and cerebral microangiopathy in a patient with Churg-Strauss syndrome.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a multisystemic disease that mainly affects the lungs and skin. It is considered to be a small and medium-vessel vasculitis. Although neurologic manifestations of EGPA are reported, usually consisting of peripheral neuropathy, central nervous system manifestations are quite rare, those described being cerebral infarctions or hemorrhages. We present the case of a 79-year-old woman diagnosed in 2016 with EGPA, being treated with Prednisone and Azathioprine, who presented to the Neurological Emergency Department with right hemiplegia, dysmetria in the left arm and right hemi-hypoesthesia. CT (computed tomography) and MRI (Magnetic resonance imaging) findings on admission described lacunar strokes. The patient presented with low creatinine clearance on admission (positive for chronic renal disease), grade III hypertension, ischemic cardiomyopathy and right calf deep vein thrombosis. The patient was started on neuroprotective and neurotrophic treatment associated with parenteral hydration, anticoagulant and hypotensive drugs. The patient's symptoms partially improved, with possibility of independently maintaining a sitting position and upright stance with unilateral sustenance at discharge. Patients suffering from vasculitides must be carefully observed in order to prevent or treat complications that may emerge.

Evidence of complement dysregulation in outer retina of Stargardt disease donor eyes.

Stargardt macular degeneration (STGD) is a central blinding disease caused by loss of or dysfunctional ABCA4 transporter in both photoreceptors and retinal pigment epithelial (RPE) cells. Toxic bisretinoid-lipofuscin buildup in the RPE cells is a pathological hallmark of STGD patients and its mouse model, the Abca4-/-. These vitamin A-derived fluorophores have been shown to induce oxidative stress, stimulate complement activity, and cause chronic inflammation of the RPE. In vivo modulation of complement regulatory pathway in the STGD mouse model has partially rescued the STGD phenotype suggesting that complement attack on the RPE is an important etiologic factor in disease pathogenesis. While bisretinoid-dependent complement activation was further evidenced in cultured RPE cells, this pathway has never been investigated directly in the context of RPE from STGD donor eyes. In the current study, we evaluate the complement reactivity in postmortem donor eyes of clinically diagnosed STGD patients. All three STGD donor eyes RPE displayed strong immunoreactivity for an antibody specific to 4-Hydroxynonenal, a lipid peroxidation byproduct. Also, unlike the control eyes, all three STGD donor eyes showed significantly increased membrane attack complex deposition on the RPE cells. In STGD eyes, increased MAC accumulation was mirrored by elevated C3 fragments internalized by the RPE and inversely correlated with the levels of complement factor H, a major complement regulatory protein. Here, we report the first direct evidence of RPE complement dysregulation as a causative factor in developing Stargardt phenotype.

Paraneoplastic Stiff Person Syndrome in Early-Stage Breast Cancer with Positive Anti-Amphiphysin Antibodies.

Stiff person syndrome (SPS) is a rare neurologic disorder, characterized by muscle rigidity and spasms. Anti-glutamic acid decarboxylase (anti-GAD) antibodies are associated with the classic form of SPS, while antibodies against amphiphysin are associated with the paraneoplastic form of the disease. We present the case of a patient with paraneoplastic SPS, presenting with muscle cramps of lower extremities that progressed to severe muscle rigidity and spasms, associated with a right breast tumor and positive anti-amphiphysin antibodies. Paraneoplastic SPS is a rare neurological disorder, challenging for the physicians both to diagnose and treat.

Geographic Atrophy: Confocal Scanning Laser Ophthalmoscopy, Histology, and Inflammation in the Region of Expanding Lesions.

Purpose: To describe the pathology of AMD in eyes with geographic atrophy (GA) using confocal scanning laser ophthalmoscopy (SLO) blue light autofluorescence (BAF), and near-infrared (IR) AF and to correlate it with the histology and immunohistochemistry analysis at the margins of the GA lesion. Methods: Enucleated, fixed eyes from seventeen donors with GA were imaged and analyzed by BAF-SLO, IRAF-SLO, and by fundus macroscopy (FM). Tissue from the margins of the GA lesions was cut and processed for resin embedding and histology or cryosectioning and fluorescence in the green and far-red channels, and immunohistochemistry to assess markers of inflammation. Isolated DNA from donors was genotyped for single nucleotide polymorphisms (SNPs) previously shown to be risk factors for the development and progression of AMD. Results: Around the leading edge of the GA lesions we observed hypertrophic RPE cells with cytoplasm filled with granules fluorescent both in the far-red and green-red channels; abundant microglia and macrophage; deposition of complement factor H (CFH) in Bruch's membrane (BM) and increased membrane attack complex (MAC) on RPE cells. Conclusions: Fluorescence imaging of cryosections of RPE cells around the leading edge of the GA lesions suggest that IRAF-SLO visualizes mostly melanin-related compounds. In addition, medium-size GA atrophy displayed the most significant changes in inflammation markers.

Lead-Free BNT-BT0.08/CoFe2O4 Core-Shell Nanostructures with Potential Multifunctional Applications.

Herein we report on novel multiferroic core-shell nanostructures of cobalt ferrite (CoFe2O4)-bismuth, sodium titanate doped with barium titanate (BNT-BT0.08), prepared by a two-step wet chemical procedure, using the sol-gel technique. The fraction of CoFe2O4 was varied from 1:0.5 to 1:1.5 = BNT-BT0.08/CoFe2O4 (molar ratio). X-ray diffraction confirmed the presence of both the spinel CoFe2O4 and the perovskite Bi0.5Na0.5TiO3 phases. Scanning electron microscopy analysis indicated that the diameter of the core-shell nanoparticles was between 15 and 40 nm. Transmission electron microscopy data showed two-phase composite nanostructures consisting of a BNT-BT0.08 core surrounded by a CoFe2O4 shell with an average thickness of 4-7 nm. Cole-Cole plots reveal the presence of grains and grain boundary effects in the BNT-BT0.08/CoFe2O4 composite. Moreover, the values of the dc conductivity were found to increase with the amount of CoFe2O4 semiconductive phase. Both X-ray photoelectron spectroscopy (XPS) and Mössbauer measurements have shown no change in the valence of the Fe3+, Co2+, Bi3+ and Ti4+ cations. This study provides a detailed insight into the magnetoelectric coupling of the multiferroic BNT-BT0.08/CoFe2O4 core-shell composite potentially suitable for magnetoelectric applications.

Fundus autofluorescence, spectral-domain optical coherence tomography, and histology correlations in a Stargardt disease mouse model.

Stargardt disease (STGD1), known as inherited retinal dystrophy, is caused by ABCA4 mutations. The pigmented Abca4-/- mouse strain only reflects the early stage of STGD1 since it is devoid of retinal degeneration. This blue light-illuminated pigmented Abca4-/- mouse model presented retinal pigment epithelium (RPE) and photoreceptor degeneration which was similar to the advanced STGD1 phenotype. In contrast, wild-type mice showed no RPE degeneration after blue light illumination. In Abca4-/- mice, the acute blue light diminished the mean autofluorescence (AF) intensity in both fundus short-wavelength autofluorescence (SW-AF) and near-infrared autofluorescence (NIR-AF) modalities correlating with reduced levels of bisretinoid-fluorophores. Blue light-induced RPE cellular damage preceded the photoreceptors loss. In late-stage STGD1-like patient and blue light-illuminated Abca4-/- mice, lipofuscin and melanolipofuscin granules were found to contribute to NIR-AF, indicated by the colocalization of lipofuscin-AF and NIR-AF under the fluorescence microscope. In this mouse model, the correlation between in vivo and ex vivo assessments revealed histological characteristics of fundus AF abnormalities. The flecks which are hyper AF in both SW-AF and NIR-AF corresponded to the subretinal macrophages fully packed with pigment granules (lipofuscin, melanin, and melanolipofuscin). This mouse model, which has the phenotype of advanced STGD1, is important to understand the histopathology of Stargardt disease.

Fighting the 'Infodemic': Legal Responses to COVID-19 Disinformation.

Online disinformation has been on the rise in recent years. A digital outbreak of disinformation has spread around the COVID-19 pandemic, often referred to as an "infodemic." Since January 2020, digital media have been both the culprits of and antidotes to misinformation. The first months of the pandemic have shown that countering disinformation online has become as important as ensuring much needed medical equipment and supplies for health workers. For many governments around the world, priority COVID-19 actions included measures such as (a) providing guidance to social media companies on taking down contentious pandemic content (e.g., India); (b) establishing special units to combat disinformation (e.g., EU, UK); and (c) criminalizing malicious coronavirus falsehood, including in relation to public health measures. This article explores the short and potential long-term effects of newly passed legislation in various countries directly targeting COVID-19 disinformation on the media, whether traditional or digital. The early actions enacted under the state-of-emergency carve new directions in negotiating the delicate balance between freedom of expression and online censorship, in particular by imposing limitations on access to information and inducing self-restraint in reporting. Based on comparative legal analysis, this article provides a timely discussion of intended and unintended consequences of such legal responses to the "infodemic," reflecting on a basic set of safeguards needed to preserve trust in online information.

LXRs regulate features of age-related macular degeneration and may be a potential therapeutic target.

Effective treatments and animal models for the most prevalent neurodegenerative form of blindness in elderly people, called age-related macular degeneration (AMD), are lacking. Genome-wide association studies have identified lipid metabolism and inflammation as AMD-associated pathogenic pathways. Given liver X receptors (LXRs), encoded by the nuclear receptor subfamily 1 group H members 2 and 3 (NR1H3 and NR1H2), are master regulators of these pathways, herein we investigated the role of LXR in human and mouse eyes as a function of age and disease and tested the therapeutic potential of targeting LXR. We identified immunopositive LXR fragments in human extracellular early dry AMD lesions and a decrease in LXR expression within the retinal pigment epithelium (RPE) as a function of age. Aged mice lacking LXR presented with isoform-dependent ocular pathologies. Specifically, loss of the Nr1h3 isoform resulted in pathobiologies aligned with AMD, supported by compromised visual function, accumulation of native and oxidized lipids in the outer retina, and upregulation of ocular inflammatory cytokines, while absence of Nr1h2 was associated with ocular lipoidal degeneration. LXR activation not only ameliorated lipid accumulation and oxidant-induced injury in RPE cells but also decreased ocular inflammatory markers and lipid deposition in a mouse model, thereby providing translational support for pursuing LXR-active pharmaceuticals as potential therapies for dry AMD.